Topical dihydrotestosterone (DHT) for promoting hair growth-containing formulations

ABSTRACT

The present invention relates to the composition and method of use for the topical application of the potent androgen hormone dihydrotestosterone (DHT), used alone or in fixed combination with other hair growth medications; including other androgens, bimatoprost, other prostamides, prostaglandins, minoxidil or apocrine hair growth factors to promote and enhance hair growth of terminal mustache hair, beard hair, also chest hair, and other male androgen sensitive or dependent hair growth in humans or animals.

CROSS-REFERENCE TO RELATED APPLICATIONS/INCORPORATION BY REFERENCE

The present application is a continuation of U.S. patent applicationSer. No. 13/986,854, filed Jun. 12, 2013, which claims priority to andthe benefit of U.S. Patent Application No. 61/689,808, filed Jun. 13,2012. The above-identified applications are hereby incorporated hereinby reference in their entirety.

BACKGROUND OF THE INVENTION

This invention seeks to solve the problem faced by many men have withweak mustaches and/or weak beard hair growth and/or weak chest hairgrowth by providing for the topical application of dihydrotestosterone(DHT), used alone or in fixed combination with other hair growthmedications; including other androgens, bimatoprost, other prostamides,prostaglandins, minoxidil or apocrine hair growth factors to promote andenhance hair growth of terminal mustache hair, beard hair, also chesthair, and other male androgen sensitive or dependent hair growth inhumans or animals.

This invention may make it possible for some men to bypass and overcometheir own hair follicle genetic limitations (as its relates to thelevels of intracellular 5 alpha reductase, and also, the number ofandrogen receptors located inside the mesenchymal dermal papilla cellsin the hair follicles of the mustache, beard and chest hair areas). Thisinvention can thus lead to more full, thick, virile, more pigmented androbust hair growth of terminal hairs in the mustache, beard and chestareas in some men.

The inventor is not aware of any U.S. Food and Drug Administrationmedications approved for the indication of promoting facial hair growthin the mustache or beard areas. Nor is he aware of any U.S. Food andDrug Administration medications approved to promote the growth ofandrogen sensitive or androgen dependent hair growth on the chest orother parts of the body.

The inventor is unaware of any patented methods for usingpharmaceuticals, medications or other synthetic or naturally occurringcompounds, approved to promote and enhance the growth of mature,terminal facial hairs in the mustache or beard areas. The same is truefor chest hair growth or other areas of androgen dependent hair growth.

This composition and method uses the topical application ofdihydrotestosterone (DHT), used alone or in fixed combination with otherhair growth medications; including other androgens, bimatoprost,prostamides, prostaglandins, minoxidil or apocrine hair growth factorsto promote and enhance hair growth of terminal mustache hair, beardhair, chest hair, and other male androgen sensitive or dependent hairgrowth in humans or animals, utilizing liquids, lotions, ointments,creams, gels, foams, sprays or aerosols or other solvents.

This invention addresses a long felt, but unmet need. For many decades,young adult men and adult men have been well aware of there lack ofability to grow strong, full and robust mustache, beard and chest hair.There have been no scientific or pharmaceutical options available tothem until now.

At birth, the average healthy human is born with 5 million hairfollicles on the body. Of these, 1 million hair follicles are located onthe head, with 100 thousand hair follicles located on the scalp area. Ofnote, scalp hair follicles, as well as eyebrow and eyelash hairfollicles are not dependent on androgen hormones to produce hair growth.After birth, no new hair follicles are created on the human skin.

All hair, both human and animal, passes through a life cycle thatincludes three phases, namely, (1) the anagen phase (2) the catagenphase and (3) the telogen phase. The anagen phase is the period ofactive hair growth and, insofar as scalp hair is concerned, thisgenerally lasts from 3-5 years. The catagen phase is a shorttransitional phase between the anagen and telogen phases which, in thecase of scalp hair, lasts only 1-2 weeks. The final phase is the telogenphase which, for all practical purposes, can be denominated a “restingphase” where all growth ceases and the hair eventually is shedpreparatory to the follicle commencing to grow a new one. Scalp hair inthe telogen phase is also relatively short-lived, some 3-4 monthselapsing before the hair is shed and a new one begins to grow.

Now, under normal hair growth conditions on the scalp, approximately 88%of the hairs are in the anagen phase, only 1% in catagen and theremainder in telogen. With the onset of male pattern baldness, asuccessively greater proportion of the hairs are in the telogen phasewith correspondingly fewer in the active growth anagen phase.

The skin is a multifunctional and multicompartment organ affected bydiseases and their treatments. The bulk of percutaneous absorption ofmost agents is through the stratum corneum, which covers the entire skinsurface. Of note, hair follicles and hair shafts can also play animportant role in absorbing topical medications and compounds applied tothe surface of the skin. Epidermal structure and sweat glands are alsopotential pathways of absorption of topically applied medications orhair growth agents. Hair follicles form a lipid-rich pathway for drugabsorption and also represent a special shunt pathway to allow for adirect pathway for topical medications to reach key hair folliclestructures and also provides a localized drug reservoir that can enhancelocal effects of medicines in the hair follicles. The absorption ofdrugs and chemicals into and onto hair shafts also can be used tomeasure prior drug exposure.

TECHNICAL FIELD OF THE INVENTION

The technical field of this invention relates to the topical use of thepotent androgen, dihydrotestosterone (DHT), used alone or in fixedcombination with other hair growth medications; including otherandrogens, bimatoprost, prostamides, prostaglandins, minoxidil orapocrine hair growth factors to promote and enhance hair growth ofterminal mustache hair, beard hair, also chest hair, and other maleandrogen sensitive or dependent hair growth in humans or animals.

The role of dihydrotestosterone (DHT) in specific hair follicle cellularactivity located in the mustache, beard, chest and androgen dependenthair follicles is well known. Both dihydrotestosterone (DHT) andtestosterone (T) are known to play an important role in the cell biologyof mesenchymal dermal papilla cells located in the bulbs of androgendependent hair follicles. Once dihydrotestosterone (DHT) andtestosterone (T) are engaged with androgen receptors in these dermalpapilla cells, they migrate into the nucleus of the cell and trigger andexpression of genetic coding that leads to the creation of many apocrinegrowth factors and other hair growth factors that lead to matureterminal hair growth in androgen dependent hair follicles.

Some scientists suggest that there are basically two types of hair, softlanugo hair called vellus hair, and a thicker, coarser hair called aterminal hair. Vellus hair is all over the body except for the palms andsoles. Hair growth can be further differentiated as being eitherandrogen dependent or androgen independent hair. This distinctionbecomes important during puberty and throughout adulthood. Otherscientists have noted an intermediate type of hair that is on thecontinuum between vellus hair and terminal hair.

Hair growth on the scalp is not dependent on androgen hormones. However,hair loss on the scalp leading to male or female pattern hair loss isoften related to both genetics and the effects of testosterone (T) anddihydrotestosterone (DHT) (as well as other factors) that lead to theloss of active scalp hair follicles that can produce either vellus orterminal hairs.

Hair growth of eyelash hair or eyebrow hair is not androgen dependent.As with scalp hair, young children with normal health are usually ableto grow scalp hair, eyelash hair and eyebrow hair before puberty.

In the epidermis, the stratum corneum is the outer layer and is 5-600microns thick. The stratum corneum is the major barrier to percutaneousabsorption of drugs and also helps minimize the loss of water from thebody. It is made of “dead” epidermal cells that cannot reproduce andhave lost their nuclei and mitochondria. It possesses multiple proteinsand lipids that may reversibly or irreversibly bind drugs. Manychemicals and physical treatments to enhance percutaneous absorptionwork within the stratum corneum. Many drugs may partition into thestratum corneum and can function as a reservoir for drugs that willdiffuse into the rest of the skin, even after topical application of thedrug has ceased. The stratum corneum varies in thickness. Facial andpost auricular have the thinnest stratum corneum.

The living layers of the epidermis with metabolically active cellscomprise a layer of˜100 microns thick. The lowest or basal layer of theepidermis is called the stratum basale and is responsible for the bulkof cell division. Several cell layers in the spinous layer (stratumspinosum) contain cells that actively synthesize most epidermalproteins, especially keratins. The uppermost layer of the livingepidermis is the stratum granulosum. This layer is where extracellularlipids are extruded from the epidermis.

There is a superficial capillary plexus of blood vessels between thedermis and epidermis that is the site of the majority of the systemicabsorption of cutaneous drugs. There are a large number of lymphatics aswell in this area.

The dermis is about 1,200 microns thick that is in part composed ofcollagen and proteoglycans that may bind drugs. Below the dermis, is asubcutaneous tissue called the hypodermis.

The hair shaft is formed by keratinized cells containing highlyorganized material. Hair has the appearance of an extremely elongatedcylinder. The hair shaft has three (3) regions: The cuticle, the cortexand the medulla found close to the center of the hair shaft.

Lanugo hairs, the first body hairs formed in the embryo, are vellus incharacter, but often longer than the vellus shafts of the adult. Thevellus hair shaft is short, thin, fine, lightly pigmented, and with nomedulla. A vellus hair follicle is defined as a small follicle thatextends no deeper than the upper dermis and produces a shaft no widerthan its internal root sheath. Although vellus follicles may lackarrector pili muscles in some areas, vellus hair follicles areassociated with these structures on the face. With maturity and exposureto androgens, regional human hair follicles switch in morphology toterminal follicles that produce terminal hair shafts. The inverseterminal-to-vellus switch occurs on the scalp of the geneticallysusceptible androgenic alopecia individuals after exposure to androgens.

The hair cycle appears to be central to the vellus-to-terminal hairfollicle switch because phenomenologically the cycle appears to initiatethat process; the follicle must cycle in order for the switch to occur.We do not yet know how the cycle is related to this transformation,although it may be due to a gradual change in the size of the papillawith the completion of each cycle. Relatively little attention has beengiven to this switch phenomenon mechanistically; in fact, even thefollicle that characteristically switches has not yet been fullycharacterized.

The wide response range of hair to androgens reflects inherent geneticdifferences of hair depending on body site. There is a graded responseof regional hairs to androgen levels; inguinal and axillary follicles,for example, are stimulated to grow under low levels of androgen, andfacial hair to high levels, while deep temporal/occipital scalp andeyebrow/eyelash hair are insensitive to androgen levels altogether. Thisprinciple underlies the success of scalp hair transplants for malepattern balding, where androgen-insensitive hairs (occipital area) aretransplanted to sites of androgen-sensitive hairs (frontal, parietal,coronal areas). Thus one must distinguish between hairs that areandrogen dependent (axilla, mustache, beard and chest), androgeninsensitive (eyebrow and eyelash), and androgen independent but androgensensitive (scalp vertex in susceptible individuals). Ultimately, theseinterfollicular and interregional differences must stem from the way agiven follicle is genetically programmed and how it responds to androgenstimulation, its androgen target genes, and the nature of its androgenreceptor-mediated signal transduction events. Unfortunately, theseparameters have not yet been dissected.

Hair growth during and after puberty of mature terminal hairs on theface in the mustache and beard areas is androgen dependent. The same istrue for terminal hair growth in the chest and other parts of the malebody. This process begins in puberty in boy who are developing secondarysex characteristics on their way to becoming young adult men.

Hair biology and hair loss physiology are complex and relate to a widerange of genetic variables, ethnic background, family history &genetics, health status, medication use, diet and even psychosocialstress levels.

The exploration and investigation of possible treatment options fortreating and promotion hair growth in men who have weak, sparse orinconsistent mustache, beard, chest and other androgen dependent hairgrowth areas requires an in depth understanding of hair biology,endocrinology, genetic hair growth variables in both sexes, and hormonalregulation of hair growth factors in different areas of the skin.

Genetics plays an important role both in the density and number of hairfollicles in the mustache, beard and chest hair areas. In addition,genetics may determine the number of androgen receptors located inindividual hair follicle cells on the face and chest. Further, geneticshelps to determine the level and activity of the enzymes 5 alphareductase 1, 2 and 3 that play an important role within the body andalso in the hair follicle cells relating to the growth of matureterminal facial hair, mustache hair, beard hair, chest hair and otherandrogen dependent hair growth.

Ethnic origin and ancestry can play an important role and have a greatimpact on the hair growth in men. This is true for facial hair growth,chest hair growth, scalp hair growth and hair growth on the entire body.

For young men and adult men who are unable to grow robust and fullbeards and mustaches, this may be related to a lack of adequate numbersof androgen receptors in hair follicle cells in the mustache, beard andchest hair areas. In addition, this problem may also be related to agenetically determined lower level of intracellular 5 alpha reductaseenzymes 1, 2 and 3 levels within hair follicle cells in the mustache,beard and chest hair areas.

It is well established that testosterone and dihydrotestosterone playkey roles in the development of classic male secondary sexcharacteristics that promotes the virilization of adolescent boys tomature adult men during adolescence and sexual maturation. In addition,both testosterone and dihydrotestosterone play important roles indeveloping fetuses, children during adolescence, early adulthood andthroughout life in both male and female humans. This is also true foranimals.

All naturally occurring androgens play a critical role in human healthand all androgens have major conversions and important metabolicpathways for interconversion into other hormones, other steroid hormonesand other sex hormones. The same is true for animals.

It is well known that at the cellular level, testosterone is routinelyconverted into to dihydrotestosterone via the enzymes five alphareductase 1, 2 and 3. This conversion of testosterone todihydrotestosterone within hair follicles, that usually happens withincells, creates a very powerful anabolic androgenic steroid hormone,dihydrotestosterone (DHT), that is 2 to 5 times more potent and powerfulthan testosterone in causing a wide range of physiologic effects in thebody. This is particularly true with regard to androgen dependent hairgrowth in the human body compared to testosterone. The same is true inanimals.

It is known that dihydrotestosterone (DHT) binds more tightly to theandrogen receptors located in cells in many parts of the body relatingto male hair growth than does testosterone (T). The conversion oftestosterone (T) to dihydrotestosterone (DHT) results in anamplification the physiologic effect of testosterone (T) with regard tofacial hair growth and chest hair growth.

While this patent application addresses the problem of weak, sparse orinconsistent hair growth in the mustache, beard, chest and otherandrogen dependent hair growth, for the most part, the vast majority ofresearch in hair biology has centered on male and female loss of hair orbaldness. A great deal of scientific effort and hard work hasinvestigated a wide number of ways to deal with both male and femalehair loss on the scalp. The enormity of the emotional pain andsuffering, the sense of lost youth, lost identity, and lost physical andsexual attractiveness caused by the loss of, or the thinning of scalphair, in both men and women is beyond calculation. Genetics plays a keyrole in determining what males and females will be impacted by mild,moderate and severe hair loss in the scalp area over their lifetimes.The complex nature of hair genetics and hair biology relating to scalphair loss is most interesting and scientists have made some early andsignificant strides in understanding the key roles of many factorsrelating to hair loss, hair growth and hair characteristics. Majorpharmaceutical companies have invested in serious hair biology researchrelated to loss of hair on the scalp. Sales of medications for reversingor slowing down human scalp hair loss have provided some men and womenwith improved scalp hair growth and also generated significant sales andprofits. Such scientific insights have included the important roles ofandrogens [in particular dihydrotestosterone (DHT) and testosterone (T)]as well as the role of the 5 alpha reductase enzymes play in leading tothe loss of scalp hairs and sometimes major hair loss on the scalpleading to significant baldness and at times the complete destruction ofhair follicles in the scalp.

However, little to no attention has been paid to the longstandingproblem of weak, sparse or less than robust facial hair growth in themustache and beard areas. While for some young adult men and adultmales, mustache and beard growth is strong and impressive, there aremany young men and adult men who are not able to grow a full beardand/or a full, thick and strong mustache. This is related to genetics,specific hair follicles genetics, and a host of other factors outside aperson's control. Maturing boys, young men and adult men learn on theirown accord as they move through puberty into early adulthood if they areable to grow both a full, thick and strong beard and mustache. Those whofind that they are unable to grow a full, thick and consistently strongmustache, and who would like to grow a mustache, have had no realmedical treatment options to enhance their potential for improving theirown ability to grow a full and more robust mustache. The same is truefor men who find that they have only been able to grow weak or spottybeards.

It is of great interest to note that some men are able to grow fairlyfull and strong beards, yet are unable to grow a full, thick and strongmustache. Many men are unable to grow a full, rich and robust mustache,beard and chest hair. This is related to their genetics, the hairbiology of key hair follicles in the mustache, beard and chest hairareas. This is well demonstrated when one observes professional hockeyplayers and football players who often do not shave during playoffsgames or championship playoff series. These professional athletes oftenput on their “game faces” on and do not shave there mustache or beardareas to appear more tough and intimidating. When watching theseexceptional athletes, it is clear that some players are able to growfull mustaches and beards. Yet others are often unable to grow strongand full mustache hair and/or beard hair. It is quite striking to seehow many professional hockey players and football players are unable togrow full, thick and robust mustache hair and beard hair. Some grow veryweak and sparse mustache and beard hair. Clearly these eliteprofessional male athletes have normal or high normal levels ofcirculating testosterone. This is just an example of what may be goingon a large scale basis for men between the ages of 18 to 65.

While the hair follicles in the beard area and mustache area are exposedto the same levels of circulating androgen hormones [particularlytestosterone (T) and dihydrotestosterone (DHT)] in males, in some men,the growth of a mustache hair never quite comes up to the level of fulland consistently thick hair growth that occurs in the beard area. Somemight designate these men as having “weak mustache hair growth syndrome”(“WMHGS”). The same is true for chest hair and for other areas of theskin where male secondary sex characteristics relating to body hairgrowth and appearance are well described.

SUMMARY OF THE INVENTION

In its most broad embodiment, the invention is a compound and method forpromoting and enhancing the growth of androgen sensitive or androgendependent hair in areas of human skin sensitive to or dependent onandrogen for growth of hair, comprising the steps of applying a topicalpharmaceutically acceptable formulation of dihydrotestosterone (DHT),used alone or in fixed combination with other hair growth medications;including other androgens, bimatoprost, prostamides, prostaglandins,minoxidil or apocrine hair growth factors to promote and enhance hairgrowth of terminal mustache hair, beard hair, also chest hair, and othermale androgen sensitive or dependent hair growth in humans or animals.The invention is applied in a topical manner to targeted skin areaswhere hair growth is desired and regularly repeating said applicationuntil desired hair growth results. This includes areas in the region ofmustache hair growth, beard hair growth, or chest hair growth.

The composition and method includes the use of dihydrotestosterone (DHT)as a topical monotherapy for the promotion and enhancement of mustache,beard, chest hair and other androgen dependent hair. The topicalcomposition of dihydrotestosterone (DHT) may be of the 1% to 25%. Thecomposition and method includes the topical application of suchformulations to adolescents or adults.

The dihydrotestosterone (DHT) topical formulations used in the method ofthe invention additionally comprises one or more additional otherandrogens, for example testosterone (T), 1 to 25%, or can additionallycomprise one or more non-steroidal alopecia treatment agents, forexample minoxidil, 2% to 5% w/v, or one or more hair growth promotersincluding prostamindes or prostaglandins, further including travoprost,latanoprost or bimatoprost 0.001% to 0.1% w/v and most preferably 0.03%w/v. These formulations can be administered as topical lotions,ointments, solutions, gels, foams, or sprays. The topical formulationsare formulated so as to deliver the active ingredient(s) to the hairfollicles and the bulb matrices of hair follicles, or to the mesenchymaldermal papilla cells of the hair follicles and also hair folliclestructures that can be reservoirs for applied formulations.

The inventor believes that it is most useful to formulate the topicalformulation so as to be able to be absorbed into the hair folliclestructures in a targeted manner. In addition, to allow the formulationto also adsorb onto a hair shaft itself and be drawn by capillary actionto the target hair follicle bulb and other hair follicle structures.Additional useful formulation properties are the ability to cross thesurface of the skin and travel to the hair follicle bulb matrix bytrans-epidermal diffusion or by transdermal diffusion, following Fickes'laws of diffusion. This is beneficially accomplished by the addition ofone or more dermal penetration enhancement agents, such as a loweralcohol, including methanol, ethanol, propanol, or isopropanol.

The most preferred embodiments of the invention utilize topicalformulations that cause the active ingredient(s) to penetrate the layersof the epid-imis and dermis sufficiently to reach the hair follicles andthe hair follicle bulb matrices, but not of such a great concentrationso as to be absorbed to a significant degree into the systemiccirculation.

Most preferred concentrations of dihydrotestosterone (DHT) run in arange of from about 0.5% to about 25%, measured w/w, /w/v, or v/v.Additional topical formulation ingredients include pharmaceuticallyacceptable preservatives such as benzalkonium chloride, 0.2 to 0.5mg/mL, sodium chloride, dibasic sodium phosphate, citric acid, andpharmaceutically acceptable purified water, eg. distilled water, reverseosmosis water, and so on. An important aspect of the present inventionis that a topical formulation can contain dihydrotestosterone as amonotherapy or in any fixed dose combination with one or more oftestosterone, minoxidil, the prostamide bimatoprost, other prostamidesand prostaglandin analogs, including travoprost, or latanoprost.

DETAILED DESCRIPTION OF THE DRAWINGS

No drawings or figures are presented.

DETAILED DESCRIPTION OF THE INVENTION

This method of use pharmaceutical invention relates to the topical useof the potent androgen dihydrotestosterone (DHT), used alone or in fixedcombination with other hair growth medications; including otherandrogens, bimatoprost, other prostamides, prostaglandins, minoxidil orapocrine hair growth factors to promote and enhance hair growth ofterminal mustache hair, beard hair, also chest hair, and other maleandrogen sensitive or dependent hair growth in humans or animals.

This invention seeks to solve the problem faced by many men have withweak mustaches and/or weak beard hair growth and/or weak chest hairgrowth by providing for the topical application of dihydrotestosterone(DHT), used alone or in fixed combination with other hair growthmedications; including other androgens, bimatoprost, other prostamides,prostaglandins, minoxidil or apocrine hair growth factors to promote andenhance hair growth of terminal mustache hair, beard hair, also chesthair, and other male androgen sensitive or dependent hair growth inhumans or animals.

This invention may make it possible for some men to bypass and overcometheir own hair follicle genetic limitations (as its relates to thelevels of hair follicle intracellular 5 alpha reductase enzyme levels &activity, and also, the number of androgen receptors located inside themesenchymal dermal papilla cells in the hair follicles of the mustache,beard and chest hair areas). This invention can thus lead to more full,thick, dense, virile, more pigmented and robust hair growth ofintermediate and/or terminal hairs in the mustache, beard and chestareas in some men.

For many men who are unable to grow a consistently full beard and/or aconsistently full and robust mustache, it may be due to the possibilitythat the underlying problem relates to a lack of, or a lack of fullexpression of, the genetically programmed enzyme, 5 alpha reductase thatexists in mesenchymal dermal papilla cells, which are located in thedermal bulb areas of the deepest part of the hair follicles located inthe mustache, beard and chest hair areas of the human body.

In addition, for some men, the number genetically programmed numbers ofandrogen receptors that are located in the mesenchymal dermal papillacells located at the base of the hair follicles in the mustache, beardand chest areas may be decreased compared to other areas where beard,mustache and chest hair growth is more active and full.

In androgen dependent hair follicles on the mustache, beard and chesthair areas, a critical conversion of testosterone (T) todihydrotestosterone (DHT) occurs due to the enzyme 5 alpha reductase.The 5 alpha reductase enzymes located with the hair follicles and themesenchymal dermal papilla cells in the hair follicles allow fortestosterone to be converted into a more potent androgen hormone,dihydrotestosterone, that can play a more powerful role in promotionhair growth activity in androgen dependent hair follicles located in themustache, beard, chest and other parts of the body.

This invention allows for the topical application of the potentandrogen, dihydrotestosterone (DHT), directly to skin surface and allowsfor the dihydrotestosterone (DHT) to reach the hair follicle structuresand the mesenchymal dermal papilla hair follicle cells located in thehair bulb via the hair shaft, the hair follicle and the skin and lead tothe increased production of mature, terminal mustache, beard and chesthair growth.

For the first time, there may now exist a topical pharmaceutical therapy(and also fixed combination therapies) that can overcome the limitationsof genetic programming of important androgen dependent hair follicles inthe mustache, beard, chest and other androgen dependent hair growthareas. This is accomplished through the use of dihydrotestosterone (DHT)in a topical manner, used alone or in fixed combination with other hairgrowth medications; including other androgens, bimatoprost, otherprostamides, prostaglandins, minoxidil or apocrine hair growth factorsto promote and enhance hair growth of terminal mustache hair, beardhair, also chest hair, and other male androgen sensitive or dependenthair growth in humans or animals.

This targeted delivery of dihydrotestosterone (DHT), used alone or incombination with other androgens, does not seek to achieve completetransdermal penetration of medication into the subcutaneous fat layerlocated beneath the dermis. The present invention seeks to achievetargeted delivery of dihydrotestosterone (DHT) to the hair folliclebulbs and mesenchymal dermal papilla cells with minimal drug reachingthe systemic circulation. This mitigates against systemic absorptions ofthe drug and reduces the possibility of adverse hair loss events in thescalp hair area and also mitigates against any significant elevation ofsystemic dihydrotestosterone (DHT) levels that could lead to prostatehyperplasia or cancer.

It may be possible that the use of targeted and topicaldihydrotestosterone (DHT) is only necessary for a period of a few weeksor months to sufficiently activate, trigger and transform vellus hairfollicles to more mature terminal hair follicles and lead to theproduction of mature, terminal hairs in the mustache, beard and chestareas so as to be a short term therapy that leads to long term results.This is called a transformation of a vellus hair follicle to a terminalhair follicle that may continue on long after the initial application ofthe dihydrotestosterone (DHT).

While the present invention may be embodied in many different forms,several specific embodiments are discussed herein with the understandingthat the present disclosure is to be considered only as anexemplification of the principles of the invention, and it is notintended to limit the invention to the embodiments illustrated. Wherethe invention is illustrated herein with particular reference todihydrotestosterone (DHT), it will be understood to those skilled in theart that any other androgen can, if desired, be substituted in whole orin part for dihydrotestosterone (DHT) in the methods herein described.

In one embodiment, the present invention is directed to a method fortopical administration of dihydrotestosterone (DHT) in a liquid. Theliquid comprises dihydrotestosterone (DHT), used alone or in combinationwith another androgen, that would be applied to the outer surface ofskin areas where a person would hope to increase facial hair growth inthe mustache of beard areas, or in the chest area. The embodiment mayinclude one or more lower alcohols, such as ethanol or isopropanol, apenetration enhancing agent such as isopropyl myristate; a thickener;and water. Additionally, the present invention may optionally includesalts, emollients, stabilizers, antimicrobials, fragrances, andpropellants.

In another embodiment, the present invention is directed to a method fortopical administration of dihydrotestosterone (DHT) in a lotion. Thelotion comprises dihydrotestosterone (DHT), used alone or in fixedcombination with other hair growth medications; including otherandrogens, bimatoprost, prostamides, prostaglandins, minoxidil orapocrine hair growth factors to promote and enhance hair growth ofterminal mustache hair, beard hair, also chest hair, and other androgensensitive or dependent hair growth in humans or animals that would beapplied to the outer surface of skin areas where a person would hope toincrease facial hair growth in the mustache of beard areas, or in thechest area. The embodiment may include one or more lower alcohols, suchas ethanol or isopropanol, a penetration enhancing agent such asisopropyl myristate; a thickener; and water. Additionally, the presentinvention may optionally include salts, emollients, stabilizers,antimicrobials, fragrances, and propellants.

Other embodiments of this invention are directed to a method for topicaladministration of dihydrotestosterone (DHT) in a cream, a gel, anaerosolized spray, foam or other manner for deliveringdihydrotestosterone (DHT), used alone or in fixed combination with otherhair growth medications; including other androgens, bimatoprost,prostamides, prostaglandins, minoxidil or apocrine hair growth factorsto promote and enhance hair growth of terminal mustache hair, beardhair, also chest hair, and other male androgen sensitive or dependenthair growth in humans or animals that can be applied to the outersurface of skin areas where a person would hope to increase facial hairgrowth in the mustache of beard areas, or in the chest area. Theembodiment may include one or more lower alcohols, such as ethanol orisopropanol, a penetration enhancing agent such as isopropyl myristate;a thickener; and water. Additionally, the present invention mayoptionally include salts, emollients, stabilizers, antimicrobials,fragrances, and propellants.

As used herein, the term “lower alcohol,” alone or in combination, meansa straight-chain or branched-chain alcohol moiety containing one toabout six carbon atoms. In one embodiment, the lower alcohol containsone to about 4 carbon atoms, and in another embodiment the lower alcoholcontains two to about 3 carbon atoms. Examples of such alcohol moietiesinclude methanol, ethanol, ethanol USP (i.e., 95% v/v), n-propanol,isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol. Asused herein, the term “ethanol” refers to C₂H₅OH. It may be used asdehydrated alcohol USP, alcohol USP, or in any common form including incombination with various amounts of water.

In one embodiment, the present invention is directed to a method forpercutaneous administration of dihydrotestosterone (DHT), used alone orin combination, in a hydroalcoholic gel. The gel comprises one or morelower alcohols, such as ethanol or isopropanol; a penetration enhancingagent; a thickener; and water. In one embodiment, the gel comprises ananionic polymer thickening agent precursor neutralized with a hydroxidereleasing agent, such as, e.g, sodium hydroxide. Additionally, thepresent invention may optionally include salts, emollients, stabilizers,antimicrobials, fragrances, and propellants.

EXAMPLES AND SCIENTIFIC STUDY DATA Example 1

In a single subject clinical trial, a 5% topical lotion ofdihydrotestosterone (DHT) was applied to the right upper facial skinarea over the upper lip where the mustache hairs normally grow in men.This study was performed in February and March 2008. In this study, a 55y.o. male who was able to grow a full beard and yet relatively modestmustache hair above the upper lip applied a white 5% dihydrotestosterone(DHT) cream to his right mustache area beginning in mid February 2008.

The 5% dihydrotestosterone (DHT) lotion was applied on a basis of 1 to 3times a day with a Q-Tip. Over the first four weeks, an assessment by aBoard Certified Dermatologist (also Board Certified in InternalMedicine) and a Professor of Medicine and M.D., Ph.D. expert in clinicalpharmacology, examined the subject in the clinical trial and both noteda positive difference with more hair growth, more pigmented hairs,longer and more stiff & rigid hairs and more mature hair growth in themustache area on the right side (treated side) mustache area. This earlyclinical data suggests that a topical application of a 5%dihydrotestosterone (DHT) compounded cream has a positive effect ingrowing more mustache hair and more mature, thicker, stiffer, longer,darker and more mature hairs in the mustache area. There were no sideeffects noted in this study during the four weeks of treatment with 5%topical dihydrotestosterone (DHT). No skin side effects and no systemicside effects were noted. The application of 5% dihydrotestosterone (DHT)cream showed no untoward side effects and was shown to effectivelypromote desired hair growth in the skin areas of concern.

Bimatoprost

Bimatoprost, a prostamide F 2 alpha analog, is now well documented inthe enhancement and promotion of certain specialized hair growthtreatments. U.S. Pat. No. 6,262,105 to Johnstone suggests thatprostamides and prostaglandin analogs and their derivatives thereof areuseful in a method of enhancing hair growth.

Bimatoprost, which is sold by Allergan, Inc. of Irvine, Calif., U.S.A.as Lumigan® ophthalmic solution, for treating glaucoma. Throughserendipity, it was found that bimatoprost to be a safe and effectivecompound to increase the growth, length and pigmentations of eyelashhairs when applied in the FDA approved manner. Allergan, Inc. marketsthis product as Latisse®.

Bimatoprost is a synthetic prostamide analog with ocular hypotensiveactivity. Its chemical name is(Z)-7-[(1R,2R,3R,5S)-3,5Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide,and its molecular weight is 415.58. Its molecular formula is C₂₄H₃₇NO₄.

Bimatoprost is a powder, which is very soluble in ethyl alcohol andmethyl alcohol and slightly soluble in water. In the glaucoma eye dropcompound, Lumigan® 0.01% and 0.03%, it is a clear, isotonic, colorless,sterile ophthalmic solution with an osmolality of approximately 290mOsmol/kg.

In the glaucoma eye drop compound, Lumigan® 0.01% contains Active:bimatoprost 0.1 mg/mL; Preservative: benzalkonium chloride 0.2 mg/mL;Inactives: sodium chloride; sodium phosphate, dibasic; citric acid; andpurified water. Sodium hydroxide and/or hydrochloric acid may be addedto adjust pH. The pH during its shelf life ranges from 6.8-7.8.

The prostamides are part of a large and continually expanding series ofpharmacologically unique neutral lipids. They are COX-2 derivedoxidation products of the endocannabinoid/endovanniloid anandamide.Prostamide pharmacology is unique and, as in the case of theendocannabinoids anandamide and 2-arachidonylglycerol, bears littleresemblance to that of the corresponding free acids. By virtue of itsclose relationship to the anti-glaucoma drug bimatoprost, a prostamide F2 alpha analog, has received the greatest research attention. aprostamide F 2 alpha analog and bimatoprost effects appear independentof prostanoid FP receptor activation, according to a litany of agoniststudies. The prostamides are electrochemically neutral biological lipidsrelated to prostaglandins, but with a terminal ethanolamide group.Prostamides appear to work in hair follicles with special prostamidereceptors in key parts of the hair follicle.

Over the past ten years, it has been discovered that bimatoprost, caneffectively enhance the growth of eyelash hairs, eyebrow hair and evenscalp hair. It has been suggested that bimatoprost, may work by having“direct effects” on dermal papilla cells and act via a prostamidereceptors located in the dermal papilla cells of the hair follicle. Inaddition, it has been suggested that bimatoprost, has “indirect effects”on both hair follicle dermal matrix cells and melanocytes located in thehair bulb and in the matrix cells located in the dermal papilla. Boththe direct and indirect effects of bimatoprost have been show to lead tothe growth of longer, more pigmented and thicker hair in the eyelash,the eyebrow and now the areas of the scalp associated with androgenicalopecia (AA).

On December 2008, the FDA Dermatologic and Ophthalmic Drugs AdvisoryCommittee voted to approve bimatoprost for the cosmetic use of darkeningand lengthening eyelashes. The medical term for this is treatment ofhypotrichosis; however, the FDA approval was for purely cosmeticpurposes. Bimatoprost is a prescription drug in the United States.

In the course of treating patients having glaucoma, treatment may onlybe appropriate in one eye. Within the course of daily practice it wasdiscovered that a patient who been treated with bimatoprost has lashesthat were longer, thicker and fuller in the treated eye than in thenon-treated eye. On examination the difference was found to be verystriking. The lashes were longer and had a more full dense appearance inthe treated eye. The lash appearance on the lids of the treated eyewould have appeared quite attractive if it represented a bilateralphenomenon. Because of its asymmetric nature, the long lashes on oneside could be construed as disturbing from a cosmetic standpoint.Because of the very unusual appearance a systematic examination of otherpatients who were taking bimatoprost in only one eye was made. It soonbecame apparent that this altered appearance was not an isolatedfinding. Comparison of the lids of patients who were taking bimatoprostin only one eye revealed subtle changes in the lashes and adjacent hairsof the bimatoprost-treated side in several patients. Definitedifferences could be identified to varying degrees in the lashes andadjacent hairs of all patients who were taking the drug on a unilateralbasis for longer than 6 months. These findings were totally unexpectedand surprising.

The finding that bimatoprost, which is a prostamide, as explained below.Bimatoprost is not a prostaglandin analog derivative, such aslatanoprost, and stimulates hair growth via prostamide receptors locatedin hair follicle cells.

The changes in the lashes after topical application of bimatoprost wereapparent on gross inspection in several patients once attention wasfocused on the issue. In those with light colored hair and lashes, thedifferences were only seen easily with the aid of the high magnificationand lighting capabilities of the slit lamp biomicroscope. In the courseof a glaucoma follow up examination, attention is generally immediatelyfocused on the eye itself. Because of the high power magnificationneeded only one eye is seen at a time and the eye is seen at a highenough power that the lashes are not in focus. At these higher powers,any lash asymmetry between the two eyes is not likely to be noticedexcept by careful systematic comparison of the lashes and adjacent hairsof the eyelids of the two eyes.

Observed parameters leading to the conclusion that more robust hairgrowth occurred in the treated area following administration ofbimatoprost were multiple. They included increased length of lashes,increased numbers of lashes along the normal lash line, increasedthickness and luster of lashes, increased auxiliary lash-like terminalhair in transitional areas adjacent to areas of normal lash growth,increased lash-like terminal hairs at the medial and lateral canthalarea, increased pigmentation of the lashes, increased numbers, increasedlength, as well as increased luster, and thickness of fine hair on theskin of the adjacent lid, and finally increased perpendicular angulationof lashes and lash-like terminal hairs. The conclusion that hair growthis stimulated by bimatoprost is thus supported not by evidence of adifference in a single parameter but is based on multiple parameters ofhair appearance in treated vs. control areas in many subjects. Thisfinding was entirely unexpected and represented a previouslyunrecognized effect of bimatoprost on stimulation of hair follicles. Themodified hairs of the lashes normally turn over slowly and are in theirresting phase longer than hair on, for example, the scalp. The abilityto cause clear differences in appearance of lashes, the ability tostimulate conversion of vellus or intermediate hair to terminal hairs intransitional areas and the ability to stimulate growth of vellus hair onthe skin indicates that bimatoprost is a diversely effective andefficacious agent for the stimulation of hair growth in eyelash hair.

Patients that are treated in or around the eye with compounds of theinvention, such as bimatoprost, regularly develop hypertrichosisincluding altered differentiation, numbers, length, thickness, curvatureand pigmentation in the region of treatment. Some examples ofrepresentative bimatoprost analog compounds useful in the practice ofthe present invention include the compounds shown in Table 1:

Table 1

-   cyclopentane    heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,    [1_(α), 2_(β), 3_(α), 5₆α]-   cyclopentane    N,N-dimethylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,    [1_(α), 2_(β), 3_(α), 5_(α)]-   cyclopentane    heptenylamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-pentenyl)-3,5-dihydroxy,    [1_(α), 2_(β), 3_(α), 5_(α)]-   cyclopentane    heptenylamide-5-cis-2-(3α-hydroxy-4-trifluoromethylphenoxy-1-trans-pentenyl)-3,    5-dihydroxy, [1_(α), 2_(β), 3_(α), 5_(α)]-   cyclopentane N-isopropyl    heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,    [1_(α), 2_(β), 3_(α), 5_(α)]-   cyclopentane N-ethyl    heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,    [1_(α), 2_(β), 3_(α), 5_(α)]-   cyclopentane N-methyl    heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,    [1_(α), 2_(β), 3_(α), 5_(α)]-   cyclopentane    heptenamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-butenyl)-3,5-dihydroxy,    [1_(α), 2_(β), 3_(α), 5_(α)]

A presently preferred compound for use in the practice of the presentinvention in a fixed dose combination with dihydrosterone iscyclopentane N-ethylheptanamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α),5_(α)], also known as bimatoprost and sold under thenames of Lumigan® and Latisse® by Allergan, Inc., California, USA.

The synthesis of the above compounds described above has been disclosedin U.S. Pat. No. 5,607,978. This patent also shows, particularly inExamples 1, 2, 5 and 7 that these compounds are prostamides, notprostaglandins, in that they do not behave as prostaglandins inart-recognized assays for prostaglandin activity. The invention thusrelates to the use of the above compounds, or the prodrugs of theseactive compounds, for treatment for the stimulation of hair growth. Asused herein, hair growth includes hair associated with the mustache,beard, chest hair and other androgen dependent hair in humans and theskin of animals.

In accordance with one aspect of the invention, the compound is mixedwith a safe dermatologically compatible vehicle or carrier. The vehiclewhich may be employed for preparing compositions of this invention maycomprise, for example, aqueous solutions such as e.g., physiologicalsalines, oil solutions or ointments. The vehicle furthermore may containdermatologically compatible preservatives such as e.g., benzalkoniumchloride, surfactants like e.g., polysorbate 80, liposomes or polymers,for example, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidoneand hyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

The invention is also related to dermatological compositions for topicaltreatment for the stimulation of hair growth which comprise an effectivehair growth stimulating amount of topical dihydrotestosterone, usedalone or in a fixed combination, with one or more compounds as definedabove and with a dermatologically compatible carrier. Effective amountsof the active compounds may be determined by one of ordinary skill inthe art but will vary depending on the compound employed, frequency ofapplication and desired result, and the compound will generally rangefrom about 0.0000001 to about 50%, by weight, of the dermatologicalcomposition, preferably, from about 0.001 to about 50%, by weight, oftotal dermatological composition, more preferably from about 0.1 toabout 30%, by weight of the composition.

The present invention finds application in all mammalian species,including both humans and animals. In humans, the compounds of thesubject invention can be applied for example, to the face, mustache,beard, and upper lip areas. In animals raised for their pelts, e.g.,mink, the compounds can be applied over the entire surface of the bodyto improve the overall pelt for commercial reasons. There may bebenefits for wool production from sheep. The process can also be usedfor cosmetic reasons in animals, e.g., applied to the skin of dogs andcats having bald patches due to mange or other diseases causing a degreeof alopecia.

The pharmaceutical compositions contemplated by this invention includepharmaceutical compositions suited for topical and local action.

The term “topical” as employed herein relates to the use of a compound,as described herein, incorporated in a suitable pharmaceutical carrier,and applied at the site of thinning hair or baldness for exertion oflocal action. Accordingly, such topical compositions include thosepharmaceutical formulations in which the compound is applied externallyby direct contact with the skin surface to be treated. Conventionalpharmaceutical forms for this purpose include liquids, lotions,ointments, liniments, creams, shampoos, pastes, jellies, sprays,aerosols, and the like, and may be applied in patches or impregnateddressings depending on the part of the body to be treated. The term“ointment” embraces formulations (including creams) having oleaginous,water-soluble and emulsion-type bases, e.g., petrolatum, lanolin,polyethylene glycols, as well as mixtures of these.

Typically, the compounds are applied repeatedly for a sustained periodof time topically on the part of the body to be treated. The preferreddosage regimen will generally involve regular, such as daily,administration for a period of treatment of at least one month, morepreferably at least three months, and most preferably at least sixmonths.

For topical use, the active compounds can be formulated in aqueousliquids, solutions, lotions, creams, ointments, foams or oils exhibitingphysiologically acceptable osmolarity by addition of pharmacologicallyacceptable buffers and salts. Such formulations may or may not,depending on the dispenser, contain preservatives such as benzalkoniumchloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid etc.as additives. Furthermore, particularly aqueous solutions may containviscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or polyalcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matrices may also be employed. Depending on theactual formulation and compound to be used, various amounts of the drugand different dose regimens may be employed. Typically, the daily amountof compound for treatment of the eyelid may be about 0.1 ng to about 100mg per eyelid.

For topical use on the skin, the compound can be advantageouslyformulated using ointments, creams, liniments or patches as a carrier ofthe active ingredient. Also, these formulations may or may not containpreservatives, depending on the dispenser and nature of use. Suchpreservatives include those mentioned above, and methyl-, propyl-, orbutyl-parahydroxybenzoic acid, betain, chlorhexidine, benzalkoniumchloride, and the like. Various matrices for slow release delivery mayalso be used. Typically, the dose to be applied on the scalp is in therange of about 0.1 ng to about 100 mg per day, more preferably about 1ng to about 10 mg per day, and most preferably about 10 ng to about 1 mgper day depending on the compound and the formulation. To achieve thedaily amount of medication depending on the formulation, the compoundmay be administered once or several times daily with or withoutantioxidants.

Example 2

A study is initiated to systematically evaluate the appearance of lashesand hair around the eyes of patients who are administering bimatoprostin only one eye. The study involves 10 subjects, 5 male, 5 female,average age 70 years, (ranging from 50-94 years). All patients haveglaucoma. Each subject is treated daily by the topical application ofone drop of bimatoprost at a dosage of 1.5.mu.g/ml/eye/day (0.03%, byweight, ophthalmic solution, sold under the names Lumigan® and Latisse®by Allergan, Irvine, Calif., U.S.A.) to the region of one eye byinstilling the drop onto the surface of the eye. The region of thefellow control eye is not treated with bimatoprost and served as acontrol.

In the course of treatment with eye drops, there is typicallyspontaneous tearing, and excess fluid from the drops and associatedtears gathers at the lid margins. In the course of wiping the drugcontaining fluid from the lid margins and adjacent lid, a thin film ofthe fluid is routinely spread to contact the adjacent skin of the lidarea. This widespread exposure of the skin around the lid to the effectof drops is regularly demonstrated in patients who develop a contactdermatitis. Typically the entire area of the upper and lower lid areinvolved with induration, erythema and edema demonstrating the regularextensive exposure of the ocular adnexa to the influence of topicallyapplied drugs.

The study is limited to subjects who have administered bimatoprost toone eye for more than 3 months. The mean duration of exposure tobimatoprost prior to assessing the parameter of lash growth between thecontrol and study eye is 129 days (range 90-254 days). Observations aremade under high magnification at the slit lamp biomicroscope.Documentation of differences between the control and treatment areas isaccomplished using a camera specially adapted for use with the slit lampbiomicroscope. The results of the observations are as follows: Length oflashes: Increased length of eyelashes is regularly observed on the sidetreated with bimatoprost. The difference in length varies fromapproximately 10% to as much as 30%. Number of lashes: Increased numbersof lashes are observed in the treated eye of each patient. In areaswhere there are a large number of lashes in the control eye, theincreased number of lashes in the bimatoprost-treated eye gave thelashes on the treated side a more thickly matted overall appearance.Auxiliary lash-like hair growth: Several patients have an apparentincrease in lash-like hair in transitional areas adjacent to areas ofnormal lash distribution. These prominent robust appear lash-like hairsappeared to be of comparable length to the actual lashes. These long,thick lash-like hairs were present in the central portion of the lids ofseveral patients in a linear arrangement just above the lash line. Hairsare present at similar locations in the control eyes but are by contrastthinner or more fine in appearance, have less luster and pigment and aremore flat against the skin of the lid typical of vellus or intermediatehairs. In several patients, lash-like terminal hairs grow luxuriantly inthe medial canthal area in the treated eye. In the corresponding controleye, vellus hairs are seen at the same location. Lash-like hairs arealso present in the lateral canthal area of the treated eye but not thecontrol eye in several subjects. Large lashes are not normally presentat the lateral canthus and the area is generally free of all but a fewoccasional very fine lashes or vellus hairs. Increased growth of vellushair on lids: Fine microscopic vellus hair is present on the skin of thelids and is easily seen with the slit lamp biomicroscope. This vellushair is typically denser adjacent to and below the lateral portion ofthe lower lids. While remaining microscopic, vellus hairs are increasedin number, appear more robust and are much longer and thicker in treatedthan in control eyes in the areas below and lateral to the lower lid.Perpendicular angulation of hairs: In areas where there are lash-likehairs above the lash line and in the medial and lateral canthal areas,the hairs are much longer, thicker and heavier. They also leave thesurface of the skin at a more acute angle, as though they are stiffer orheld in a more erect position by more robust follicles. This greaterincline, pitch, rise or perpendicular angulation from the skin surfacegives the appearance of greater density of the hairs.

The foregoing observations clearly establish that bimatoprost can beused to increase the growth of eyelash hair in humans. This conclusionis based on the regular and consistent finding of manifestations ofincreased hair growth in treated vs. control areas in human subjects.The conclusion that the drug bimatoprost is capable of inducingincreased robust growth of eyelash hair is based not on a singleparameter, i.e., length, but is based on multiple lines of evidence asdescribed in the results. Detailed examination and description ofmultiple parameters of differences in hair is greatly facilitated by theability to examine the hairs at high magnification under stableconditions of fixed focal length and subject position utilizing thecapabilities of the slitlamp biomicroscope.

Example 3

A topical cream is prepared as follows: Tegacid and spermaceti aremelted together at a temperature of 70-80° C. Methylparaben is dissolvedin about 500 gm of water and propylene glycol, polysorbate 80, andbimatoprost are added in turn, maintaining a temperature of 75-80° C.The methylparaben mixture is added slowly to the Tegacid and spermacetimelt, with constant stirring. The addition is continued for at least 30minutes with additional stirring until the temperature has dropped to40-45° C. Finally, sufficient water is added to bring the final weightto 1000 gm and the preparation stirred to maintain homogeneity untilcooled and congealed.

Example 4

A topical cream is prepared as follows: Tegacid and spermaceti aremelted together at a temperature of 70-80° C. Methylparaben is dissolvedin water and propylene glycol, polysorbate 80, and bimatoprost are addedin turn, maintaining a temperature of 75-80° C. The methylparabenmixture is added slowly to the Tegacid and spermaceti melt, withconstant stirring. The addition is continued for at least 30 minuteswith additional stirring until the temperature has dropped to 40-45° C.Finally, sufficient water is added to bring the final weight to 1000 gmand the preparation stirred to maintain homogeneity until cooled andcongealed.

The composition is applied to bald human scalp once daily to stimulatethe growth of hair.

Example 5

An ointment containing 2% by weight bimatoprost is prepared as follows:White petrolatum and wool fat are melted, strained and liquid petrolatumis added thereto. The bimatoprost, zinc oxide, and calamine are added tothe remaining liquid petrolatum and the mixture milled until the powdersare finely divided and uniformly dispersed. The mixture is stirred intothe white petrolatum, melted and cooled with stirring until the ointmentcongeals. The foregoing ointment can be applied topically to mammalianskin for increased rate of hair growth, and can be prepared by omittingthe zinc oxide and calamine.

Example 6

A dermatological ophthalmic ointment containing 10% by weightbimatoprost is prepared by adding the active compound to light liquidpetrolatum. White petrolatum is melted together with wool fat, strained,and the temperature adjusted to 45-50° C. The liquid petrolatum slurryis added and the ointment stirred until congealed. Suitably the ointmentis packaged in 30 gm tubes. The foregoing ointment can be applied to theeyelid to enhance the growth of eyelashes. Similarly the composition canbe applied to the brow for eyebrow growth.

Example 7

An aqueous solution containing 5%, by weight, bimatoprost is prepared asfollows. Bimatoprost is dissolved in water and the resulting solution issterilized by filtration. The solution is aseptically filled intosterile containers. The composition so prepared can be used in thetopical treatment of baldness by application to the scalp daily.

Example 8

A sample of bimatoprost is dissolved in the vehicle ofN-methylpyrrolidone and propylene glycol. The composition can be usedfor application to dogs or cats having hair loss due to mange oralopecia of other causes.

Example 9

An aerosol containing approximately 0.1% by weight bimatoprost isprepared by dissolving the bimatoprost in absolute alcohol. Theresulting solution filtered to remove particles and lint. This solutionis chilled to about minus 30° C. To the solution is added a chilledmixture of dichlorodifluoromethane and dichlorotetrafluoroethane.

Thirteen ml plastic-coated amber bottles are cold filled with 11.5 gmeach of the resulting solution and capped. The composition can besprayed on the scalp daily to stimulate the growth of hair.

Example 10

A powder of the compound bimatoprost is prepared by mixing in dry formwith talcum powder at a weight/weight ratio of 1:10. The powderedmixture is dusted on the fur of minks or other commercially valuable furbearing animals and show animals for increased rate of hair growth.

Example 11

Following the procedure of the preceding examples, compositions aresimilarly prepared substituting an equimolar amount of a compound ofTable 1 for the bimatoprost disclosed in the preceding Examples. Similarresults are obtained. While the preferred embodiment of the inventionhas been illustrated and described, it will be appreciated that variouschanges can be made therein without departing from the spirit and scopeof the invention.

Minoxidil

Use of the compound minoxidil is now well documented in the enhancementand promotion of certain specialized hair growth treatments. Minoxidilhas been show to slow down rate and androgenic alopecia and in somecases help regrow new hair on the scalp. Generally, minoxidil has beenonly able to grow vellus hair.

Minoxidil is an antihypertensive vasodilator medication. It also slowsor stops hair loss and promotes hair regrowth. Now off-patent, it isavailable over-the-counter for the treatment of androgenic alopecia.Minoxidil must be used indefinitely for continued support of existinghair follicles and the maintenance of any experienced hair regrowth. Itis marketed under many trade names.

It has a formula C₉H₁₅N₅O. It has a molecular weight of 209.251 g/mol

Originally, minoxidil was used exclusively as an oral drug (with thetrade name Loniten®) to treat high blood pressure. However, it wasdiscovered to have an interesting side effect: hair growth. Minoxidilmay cause increased growth or darkening of fine body hairs, or in somecases, significant hair growth. When the medication is discontinued, thehair loss will return to normal rate within 30 to 60 days. UpjohnCorporation produced a topical solution that contained 2% minoxidil tobe used to treat baldness and hair loss, under the brand name Rogaine®in the United States and Canada, and Regaine® in Europe and theAsia-Pacific. The patent on minoxidil expired Feb. 11, 1996. Treatmentsusually include a 5% concentration solution that is designed for men,and a 2% concentration solution for women. While the drug is availablein the United Kingdom, it cannot be prescribed on the NHS, so patientsmust either buy it over-the-counter or have a private prescription forit.

The mechanism by which minoxidil promotes hair growth is not fullyunderstood. Minoxidil contains the nitric oxide chemical moiety and mayact as a nitric oxide agonist. Similarly, minoxidil is a potassiumchannel opener, causing hyperpolarization of cell membranes. Minoxidilis less effective when there is a large area of hair loss. In addition,its effectiveness has largely been demonstrated in younger men who haveexperienced hair loss for less than 5 years. Minoxidil use is indicatedfor central (vertex) hair loss only. Minoxidil is also a vasodilator.Hypothetically, by widening blood vessels and opening potassiumchannels, it allows more oxygen, blood, and nutrients to the follicle.This may cause follicles in the telogen phase to shed, which are thenreplaced by thicker hairs in a new anagen phase.

Minoxidil when taken orally has been known to induce hair growth inextensive areas of the back, trunk, limbs and even occasionally on theface. Such hair is of intermediate status in that it is coarser thanvellus but not as coarse as terminal hair. The hair is generally quiteshort with a length of 3 cm. being about maximum. Once the patientceases taking the drug, the hair reverts to whatever is normal for theparticular site after six months to a year has elapsed.

An example of such a drug is diphenylhydantoin which is ananticonvulsant drug widely used to control epileptic seizures.Hypotrichosis is frequently observed in epileptic children some two orthree months after starting the drug and first becomes noticeable on theextensor aspects of the limbs and later on the trunk and face. (The samepattern of hypotrichosis is sometimes caused by injury to the head.) Asfor the hair, it is often shed when the drug is discontinued but may, insome circumstances, remain.

Streptomycin is another drug that has been found to producehypotrichosis, in much the same way as diphenylhydantoin, whenadministered to children suffering from tuberculous meningitis. Aboutthe same effects were observed and the onset and reversal of thehypotrichosis in relation to the period of treatment with the antibioticleave little question but that it was the causative agent.

In addition to the foregoing, it has been reported in U.S. Pat. Nos.4,139,619 and 4,968,812, that the compound minoxidil is useful for thetreatment of male pattern baldness. That compound, among others, hasproven to have considerable therapeutic value in the treatment of severehypertension. It is a so-called anti-hypertensive “vasodilator” which,as the name implies, functions to dilate the peripheral vascular system.First introduced as an oral drug to treat high blood pressure, topicalsolutions and foam products were introduced to prevent or treat hairloss. Dermatologists and others have recognized that prolongedvasodilatation of certain areas of the human body other than the scalpsometimes result in increased hair growth even in the absence of anyvasodilating therapeutic agent. For instance, increased hair growtharound surgical scars is not uncommon. Similarly, arteriovenous fistulahave been known to result in increased vascularity accompanied byenhanced hair growth. Externally-induced vasodilation of the skin, suchas, for example, by repeated biting of the limbs by the mentallyretarded and localized stimulation of the shoulders by water carries hasbeen known to bring on hypotrichosis in the affected areas. Be that asit may, similar techniques such as continued periodic massage of thescalp have been found to be totally ineffective as a means for restoringlost hair growth to the scalp. Scar tissue on the scalp inhibits ratherthan promotes hair growth.

An alternative embodiment of the present invention providespharmaceutical fixed compositions for topical application to enhancehair growth comprising an effective amount dihydrotestosterone withcyclopentane N-ethylheptanamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α),5_(α)], also known as bimatoprost, along withminoxidil.

Another aspect of the invention provides methods for stimulating therate of hair growth and for stimulating the conversion of vellus hair orintermediate hair to growth as terminal hair in a human or non-human byadministering to the skin an effective amount of dihydrotestosterone,bimatoprost and minoxidil, wherein the additional combination ofbimatoprost and minoxidil obtains the above results in a synergisticmanner as compared to bimatoprost and minoxidil, alone.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein refers to that amountof the therapeutic agent sufficient to ameliorate one or more aspects ofthe disorder. The result can be reduction and/or alleviation of thesigns, symptoms, or causes of a disease, or any other desired alterationof a biological system. For example, an “effective amount” fortherapeutic uses is the amount of the composition comprising an agent asset forth herein required to provide a clinically significant decreasein an ophthalmic disease. For example, for the given aspect (e.g.,length of incidence), a therapeutically effective amount will show anincrease or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%,75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also beexpressed as “-fold” increase or decrease.

For example, a therapeutically effective amount can have at least a1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

Other Discussion

Treating” or “treatment” as used herein (and as well-understood in theart) also broadly includes any approach for obtaining beneficial ordesired results in a subject's condition, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (i.e., notworsening) the state of disease, prevention of a disease's transmissionor spread, delay or slowing of disease progression, amelioration orpalliation of the disease state, diminishment of the reoccurrence ofdisease, and remission, whether partial or total and whether detectableor undetectable. In other words, “treatment” as used herein includes anycure, amelioration, or prevention of a disease. Treatment may preventthe disease from occurring; inhibit the disease's spread; relieve thedisease's symptoms (e.g., ocular pain, seeing halos around lights, redeye, very high intraocular pressure), fully or partially remove thedisease's underlying cause, shorten a disease's duration, or do acombination of these things.

“Treating” and “treatment” as used herein include prophylactictreatment. Treatment methods include administering to a subject atherapeutically effective amount of an active agent. The administeringstep may consist of a single administration or may include a series ofadministrations. The length of the treatment period depends on a varietyof factors, such as the severity of the condition, the age of thepatient, the concentration of active agent, the activity of thecompositions used in the treatment, or a combination thereof. It willalso be appreciated that the effective dosage of an agent used for thetreatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may resultand become apparent by standard diagnostic assays known in the art. Insome instances, chronic administration may be required. For example, thecompositions are administered to the subject in an amount and for aduration sufficient to treat the patient.

The term “disease” refers to any deviation from the normal health of amammal and includes a state when disease symptoms are present, as wellas conditions in which a deviation (e.g., infection, gene mutation,genetic defect, etc.) has occurred, but symptoms are not yet manifested.According to the present invention, the methods disclosed herein aresuitable for use in a patient that is a member of the Vertebrate class,Mammalia, including, without limitation, primates, livestock anddomestic pets (e.g., a companion animal). Typically, a patient will be ahuman patient.

As used herein, “topical application,” “topical administration,” and“topically administering” are used interchangeably herein and includethe administration of a composition to the upper and/or lower eyelidmargin, eyebrow region, scalp or face. Topical application oradministering may result in the delivery of an active agent to the eyeor skin or a localized region of the body.

“Topical formulation” and “topical pharmaceutical composition” are usedinterchangeably herein and include a formulation that is suitable fortopical application to the face, upper lip or chest areas. Specifictopical formulations can be used for topical, local, regional, ortransdermal application of substances.

As used herein, the terms “application,” “apply,” and “applying” used inreference to a topical composition product or method of using acomposition or a product, refer to any manner of administering a topicalcomposition or a product to the eye, the mucosal or dermal area proximalto the eye of a patient which, in medical or cosmetology practice,delivers the composition or the product to patient's eye, the mucosal ordermal area proximal to the eye. Smearing, rubbing, spreading, sprayinga topical composition, with or without the aid of suitable devices, on apatient's skin are all included within the scope of the term“application,” as used herein. The term “topical” or “topically” inreference to administration or application of a composition or a productrefers to epicutaneous administration or application, or administrationonto skin. The term “topically active agent” as used herein refers to acompound that is effective in a treatment of a skin condition whenadministered topically. It is to be understood that topically activeagent can have a local or a systemic effect, or both, when administeredtopically. The term “topical,” when used in reference to a compositionor a product refers to a composition or a product formulated for topicalapplication.

The abbreviations used herein have their conventional meaning within thechemical, biological or pharmaceutical arts.

The terms “about” and “approximately equal” are used herein to modify anumerical value and indicate a defined range around that value. If “X”were the value, “about X” or “approximately equal to X” would generallyindicate a value from 0.90X to 1.10X. Any reference to “about X”minimally indicates at least the values X, 0.90X, 0.91X, 0.92X, 0.93X,0.94X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X,1.05X, 1.06X, 1.07X, 1.08X, 1.09X, and 1.10X. Thus, “about X” isintended to disclose, e.g., “0.98X.” When “about” is applied to thebeginning of a numerical range, it applies to both ends of the range.Thus, “from about 6 to 8.5” is equivalent to “from about 6 to about8.5.” When “about” is applied to the first value of a set of values, itapplies to all values in that set. Thus, “about 7, 9, or 11%” isequivalent to “about 7%, about 9%, or about 11%.” “About” may alsoinclude variations in the amount that a regulatory body such as the FDAor EMEA would view as bioequivalent to the claimed amount.

As used herein, the phrase “pharmaceutically acceptable salts” refers tosalts of the active compound(s) which possess the same pharmacologicalactivity as the active compound(s) and which are neither biologicallynor otherwise undesirable. A salt can be formed with, for example,organic or inorganic acids. Non-limiting examples of suitable acidsinclude acetic acid, acetylsalicylic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid,bisulfic acid, boric acid, butyric acid, camphoric acid, camphorsulfonicacid, carbonic acid, citric acid, cyclopentanepropionic acid, digluconicacid, dodecylsulfic acid, ethanesulfonic acid, formic acid, fumaricacid, glyceric acid, glycerophosphoric acid, glycine, glucoheptanoicacid, gluconic acid, glutamic acid, glutaric acid, glycolic acid,hemisulfic acid, heptanoic acid, hexanoic acid, hippuric acid,hydrobromic acid, hydrochloric acid, hydroiodic acid,hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, mucic acid,naphthylanesulfonic acid, naphthylic acid, nicotinic acid, nitrous acid,oxalic acid, pelargonic, phosphoric acid, propionic acid, saccharin,salicylic acid, sorbic acid, succinic acid, sulfuric acid, tartaricacid, thiocyanic acid, thioglycolic acid, thiosulfuric acid, tosylicacid, undecylenic acid, naturally and synthetically derived amino acids.Non-limiting examples of base salts include ammonium salts; alkali metalsalts, such as sodium and potassium salts; alkaline earth metal salts,such as calcium and magnesium salts; salts with organic bases, such asdicyclohexylamine salts; methyl-D-glucamine; and salts with amino acids,such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups can be quatemized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides,bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl,dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides; asthma halides,such as benzyl and phenethyl bromides; and others.

“Prodrugs” refer to compounds which are a precursor of a compound andthat is converted into its active form, for example, in the body bynormal metabolic processes. Alopecia (baldness) a deficiency of eithernormal or abnormal hair is primarily a cosmetic problem in humans. It isa deficiency of terminal hair, the broad diameter, colored hair that isreadily seen. However, in the so-called bald person although there is anoticeable absence of terminal hair, the bald scalp skin may containvellus hair which is a fine colorless hair which may require microscopicexamination to determine its presence. This vellus hair is a precursorto terminal hair. In some case of scalp alopecia, hair follicles havebeen destroyed by the long term impact of 5 alpha reductase and theimpact of dihydrotestosterone, and other factors.

Drug synergism occurs when drugs can interact in ways that enhance,magnify or synergistically amplify one or more desired effects, or sideeffects, of those drugs. Negative effects of synergy are a form ofcontraindication such as when more than one depressant drug is used thataffects the central nervous system (CNS), an example being alcohol andValium. The combination can cause a greater reaction than simply the sumof the individual effects of each drug if they were used separately. Inthis particular case, the most serious consequence of drug synergy isexaggerated respiratory depression, which can be fatal if leftuntreated.

Synergism has also been noted in describing how complex systems operate.For example, biological systems may react in a non-linear way toperturbations, so that the outcome may be greater than the sum of theindividual component alterations.

In describing the present invention, synergism means that thecombination of the two active drugs, utilized in the methods andcompositions of the invention achieves a result, e.g. stimulating thegrowth of hair such as eyelashes, in a mammal, e.g. a human, that isgreater than the result achieved when the active drugs are utilized,alone, under the same conditions. Thus, to determine the combinationsthat are within the scope of the present invention, one may simplycompare the result achieved by the combination of the two drugs with theresult achieved with each of the individual drugs, alone.

In accordance with the invention as described herein, there is provideda method for enhancing hair growth in a mammal in need thereof whichcomprises administering to the mammal a synergistically effective amountof dihydrotestosterone, testosterone, bimatoprost other prostamides orminoxidil. Thus, in accordance with the present invention,synergistically effective amounts of testosterone and/or, bimatoprostand/or minoxidil, other prostamides and/or are used withdihydrotestosterone to stimulate the conversion of vellus hair to growthas terminal hair as well as increase the rate of growth of terminal hairin the mustache, beard, chest and other androgenic dependent hair growthareas.

In said method of this invention, the concentration of added bimatoprostand/or minoxidil are administered as a composition comprising from0.0000001% to 10% bimatoprost and from 0.001% to 10% minoxidil, byweight.

Some concentrations of minoxidil include from about 0.001 to about 5 toabout 10% w/w, from about 0.005 to about 5, from about 0.01 to about 5,from about 0.05 to about 5, from about 0.1 to about 5, from about 0.5 toabout 5, from about 1 to about 5, from about 1.5 to about 5, from about2 to about 5, from about 2.5 to about 5, from about 3 to about 5, fromabout 3.5 to about 5, from about 4 to about 5, from about 4.5, fromabout 0.001 to about 4.5, from about 0.005 to about 4.5, from about 0.01to about 4.5, from about 0.05 to about 4.5, from about 0.1 to about 4.5,from about 0.5 to about 4.5, from about 1 to about 4.5, from about 1.5to about 4.5, from about 2 to about 4.5, from about 2.5 to about 4.5,from about 3 to about 4.5, from about 3.5 to about 4.5, from about 4 toabout 4.5, from about 0.001 to about 4, from about 0.005 to about 4,from about 0.01 to about 4, from about 0.05 to about 4, from about 0.1to about 4, from about 0.5 to about 4, from about 1 to about 4, fromabout 1.5 to about 4, from about 2 to about 4, from about 2.5 to about4, from about 3 to about 4, from about 3.5 to about 4, from about 0.001to about 3.5, from about 0.005 to about 3.5, from about 0.01 to about3.5, from about 0.05 to about 3.5, from about 0.1 to about 3.5, fromabout 0.5 to about 3.5, from about 1 to about 3.5, from about 1.5 toabout 3.5, from about 2 to about 3.5, from about 2.5 to about 3.5, fromabout 3 to about 3.5, from about 0.001 to about 3, from about 0.005 toabout 3, from about 0.01 to about 3, from about 0.05 to about 3, fromabout 0.1 to about 3, from about 0.5 to about 3, from about 1 to about3, from about 1.5 to about 3, from about 2 to about 3, from about 2.5 toabout 3, from about 0.001 to about 2.5, from about 0.005 to about 2.5,from about 0.01 to about 2.5, from about 0.05 to about 2.5, from about0.1 to about 2.5, from about 0.5 to about 2.5, from about 1 to about2.5, from about 1.5 to about 2.5, from about 2 to about 2.5, from about0.001 to about 2, from about 0.005 to about 2, from about 0.01 to about2, from about 0.05 to about 2, from about 0.1 to about 2, from about 0.5to about 2, from about 1 to about 2, from about 1.5 to about 2, fromabout 0.001 to about 1.5, from about 0.005 to about 1.5, from about 0.01to about 1.5, from about 0.05 to about 1.5, from about 0.1 to about 1.5,from about 0.5 to about 1.5, from about 1 to about 1.5, from about 0.001to about 1, from about 0.005 to about 1, from about 0.01 to about 1,from about 0.05 to about 1, from about 0.1 to about 1, from about 0.5 toabout 1, from about 0.001 to about 0.5, from about 0.005 to about 0.5,from about 0.01 to about 0.5, from about 0.05 to about 0.5, from about0.1 to about 0.5, from about 0.001 to about 0.1, from about 0.005 toabout 0.1, from about 0.01 to about 0.1, from about 0.05 to about 0.1,from about 0.001 to about 0.05, from about 0.005 to about 0.05, fromabout 0.01 to about 0.05, or from about 0.001 to about 0.005% (w/w). Insome embodiments, the minoxidil is present at about 0.001, 0.005, 0.01,0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% (w/w).

Minoxidil may also be present in 5.5% w/w to about 10% w/w, from about6% w/w to about 10% w/w, from about 6.5% w/w to about 10% w/w, fromabout 7% w/w to about 10% w/w, from about 7.5% w/w to about 10% w/w,from about 8% w/w to about 10% w/w, from about 8.5% w/w to about 10%w/w, from about 9% w/w to about 10% w/w, from about 9.5% w/w to about10% w/w, from about 5% w/w to about 9.5% w/w, 5.5% w/w to about 9.5%w/w, from about 6% w/w to about 9.5% w/w, from about 6.5% w/w to about9.5% w/w, from about 7% w/w to about 9.5% w/w, from about 7.5% w/w toabout 9.5% w/w, from about 8% w/w to about 9.5% w/w, from about 8.5% w/wto about 9.5% w/w, from about 9% w/w to about 9.5% w/w, from about 5%w/w to about 9% w/w, 5.5% w/w to about 9% w/w, from about 6% w/w toabout 9% w/w, from about 6.5% w/w to about 9% w/w, from about 7% w/w toabout 9% w/w, from about 7.5% w/w to about 9% w/w, from about 8% w/w toabout 9% w/w, from about 8.5% w/w to about 9% w/w, from about 5% w/w toabout 8.5% w/w, 5.5% w/w to about 8.5% w/w, from about 6% w/w to about8.5% w/w, from about 6.5% w/w to about 8.5% w/w, from about 7% w/w toabout 8.5% w/w, from about 7.5% w/w to about 8.5% w/w, from about 8% w/wto about 8.5% w/w, from about 5% w/w to about 8% w/w, 5.5% w/w to about8% w/w, from about 6% w/w to about 8% w/w, from about 6.5% w/w to about8% w/w, from about 7% w/w to about 8% w/w, from about 7.5% w/w to about8% w/w, from about 5% w/w to about 7.5% w/w, 5.5% w/w to about 7.5% w/w,from about 6% w/w to about 7.5% w/w, from about 6.5% w/w to about 7.5%w/w, from about 7% w/w to about 7.5% w/w, from about 5% w/w to about 7%w/w, 5.5% w/w to about 7% w/w, from about 6% w/w to about 7% w/w, fromabout 6.5% w/w to about 7% w/w, from about 5% w/w to about 6.5% w/w,5.5% w/w to about 6.5% w/w, or from about 6% w/w to about 6.5% w/w. Insome embodiments, minoxidil is present at about 5, 5.5, 6, 6.5, 7, 7.5,8, 8.5, 9, 9.5 or 10% (w/w).

Formulating Fixed Dose Combinations

Bimatoprost, as recited above and here presented in greater detail, maybe present at 0.1 or 0.3% w/v. Other concentrations that bimatoprost maybe present are about 0.005 to about 5, from about 0.01 to about 5, fromabout 0.05 to about 5, from about 0.1 to about 5, from about 0.5 toabout 5, from about 1 to about 5, from about 1.5 to about 5, from about2 to about 5, from about 2.5 to about 5, from about 3 to about 5, fromabout 3.5 to about 5, from about 4 to about 5, from about 4.5, fromabout 0.001 to about 4.5, from about 0.005 to about 4.5, from about 0.01to about 4.5, from about 0.05 to about 4.5, from about 0.1 to about 4.5,from about 0.5 to about 4.5, from about 1 to about 4.5, from about 1.5to about 4.5, from about 2 to about 4.5, from about 2.5 to about 4.5,from about 3 to about 4.5, from about 3.5 to about 4.5, from about 4 toabout 4.5, from about 0.001 to about 4, from about 0.005 to about 4,from about 0.01 to about 4, from about 0.05 to about 4, from about 0.1to about 4, from about 0.5 to about 4, from about 1 to about 4, fromabout 1.5 to about 4, from about 2 to about 4, from about 2.5 to about4, from about 3 to about 4, from about 3.5 to about 4, from about 0.001to about 3.5, from about 0.005 to about 3.5, from about 0.01 to about3.5, from about 0.05 to about 3.5, from about 0.1 to about 3.5, fromabout 0.5 to about 3.5, from about 1 to about 3.5, from about 1.5 toabout 3.5, from about 2 to about 3.5, from about 2.5 to about 3.5, fromabout 3 to about 3.5, from about 0.001 to about 3, from about 0.005 toabout 3, from about 0.01 to about 3, from about 0.05 to about 3, fromabout 0.1 to about 3, from about 0.5 to about 3, from about 1 to about3, from about 1.5 to about 3, from about 2 to about 3, from about 2.5 toabout 3, from about 0.001 to about 2.5, from about 0.005 to about 2.5,from about 0.01 to about 2.5, from about 0.05 to about 2.5, from about0.1 to about 2.5, from about 0.5 to about 2.5, from about 1 to about2.5, from about 1.5 to about 2.5, from about 2 to about 2.5, from about0.001 to about 2, from about 0.005 to about 2, from about 0.01 to about2, from about 0.05 to about 2, from about 0.1 to about 2, from about 0.5to about 2, from about 1 to about 2, from about 1.5 to about 2, fromabout 0.001 to about 1.5, from about 0.005 to about 1.5, from about 0.01to about 1.5, from about 0.05 to about 1.5, from about 0.1 to about 1.5,from about 0.5 to about 1.5, from about 1 to about 1.5, from about 0.001to about 1, from about 0.005 to about 1, from about 0.01 to about 1,from about 0.05 to about 1, from about 0.1 to about 1, from about 0.5 toabout 1, from about 0.001 to about 0.5, from about 0.005 to about 0.5,from about 0.01 to about 0.5, from about 0.05 to about 0.5, from about0.1 to about 0.5, from about 0.001 to about 0.1, from about 0.005 toabout 0.1, from about 0.01 to about 0.1, from about 0.05 to about 0.1,from about 0.001 to about 0.05, from about 0.005 to about 0.05, fromabout 0.01 to about 0.05, or from about 0.001 to about 0.005% (w/w). Insome embodiments, bimatoprost is present at about 0.001, 0.005, 0.01,0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% (w/w).

In a further aspect of the invention, there is provided a method foralleviating a condition characterized by inadequate or lack of hair, inor on a warm-blooded animal, which comprises topically or otherwiselocally administering to said animal an effective amount of apharmaceutical composition comprising: (1) a combination ofdihydrotestosterone, and/or other androgens, and/or bimatoprost, and/orother prostamides, and/or prostaglandins, and/or minoxidil in asynergistically effective amount and (2) a non-toxic, pharmaceuticallyacceptable carrier therefore suitable for topical or other localapplication.

In accordance with one aspect of the invention, the drugsdihydrotestosterone, testosterone, bimatoprost and/or minoxidil, aremixed with a dermatologically compatible vehicle or carrier. The vehiclewhich may be employed for preparing compositions of this invention maycomprise, for example, aqueous solutions such as e.g., physiologicalsalines, oil solutions or ointments. The vehicle furthermore may containdermatologically compatible preservatives such as e.g., benzalkoniumchloride, surfactants like e.g., polysorbate 80, liposomes or polymers,for example, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidoneand hyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

The invention is also related to dermatological compositions for topicaltreatment for the stimulation of hair growth, which comprise aneffective hair growth stimulating amount of dihydrotestosterone,testosterone, bimatoprost and/or minoxidil and a dermatologicallycompatible carrier. Effective amounts of the active compounds may bedetermined by one of ordinary skill in the art but will vary dependingon the frequency of application and desired result, and bimatoprost willrange from about 0.0000001 to about 10%, by weight, of thedermatological composition, preferably from about 0.001 to about 10%, byweight, of total dermatological composition, more preferably from about0.03 to about 5%, by weight, of the composition and minoxidil will rangefrom about 0.001 to about 10%, by weight, of the dermatologicalcomposition, preferably from about 0.01 to about 10%, by weight, of thecomposition.

The following specific combinations of bimatoprost and minoxidil in adermatologically compatible carrier are contemplated as being effectivewhen combined with dihydrotestosterone to achieve the object of thisinvention, i.e. enhancing hair growth in a mammal in need thereof byadministering to the mammal an effective amount of bimatoprost andminoxidil: Certain of these combinations may be synergistic. Otherspecific combinations within the scope of the concentrations, givenbelow, i.e. 0.1 to 10 percent minoxidil and 0.01 and 0.5 bimatoprost arealso contemplated as useful in the method of the present invention.

TABLE I Bimatoprost Weight percent Minoxidil w/w Weight percent w/w 0.01any one of 0.1, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10.0;0.02 and any one of 0.1, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and10.0; 0.03 and any one of 0.1, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0,9.0 and 10.0; 0.04 and any one of 0.1, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0,7.0, 8.0, 9.0 and 10.0; 0.05 and any one of 0.1, 1.0, 2.0, 3.0, 4.0,5.0, 6.0, 7.0, 8.0, 9.0 and 10.0; 0.1 and any one of 0.1, 1.0, 2.0, 3.0,4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10.0; 0.2 and any one of 0.1, 1.0, 2.0,3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10.0; 0.3 and any one of 0.1, 1.0,2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10.0; 0.5 and any one of 0.1,1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10.0 and 1.0 and any oneof 0.1, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10.0.

In particular, the following specific combinations of bimatoprost andminoxidil in a dermatologically compatible carrier are contemplated asbeing effective to achieve the object of this invention, i.e. enhancinghair growth in a human and non human mammal in need thereof byadministering to the mammal an effective amount of bimatoprost andminoxidil:

TABLE 2 Bimatoprost Minoxidil Weight Weight percent w/w percent w/w 0.010.1 0.01 1.0 0.02 2.0 0.03 3.0 0.04 4.0 0.05 5.0 0.06 6.0 0.07 7.0 0.18.0 0.3 9.0 0.5 10.0

Example 12

A study is initiated to systematically evaluate the appearance of lashesand hair around the eyes of patients by administering a topicalcomposition comprising 0.03% bimatoprost and 5% minoxidil, by weight, inthe area of the eyelid of only one eye. The study involves 10 subjects,5 male, 5 female, average age 70 years, (ranging from 50-94 years). Eachsubject is treated daily by the topical application of one drop ofbimatoprost at a dosage of 1.5 μg/ml/eye/day to the region of one eye byinstilling the drop onto the surface of the eyelid. The region of thefellow control eye is not treated and served as a control.

Observations are made under high magnification at the slit lampbiomicroscope. Documentation of differences between the control andtreatment areas is accomplished using a camera specially adapted for usewith the slit lamp biomicroscope.

The results of the observations will be as follows:

-   Length of lashes: Increased length of eyelashes is regularly    observed on the side treated with bimatoprost. The difference in    length varies from approximately 10% to as much as 30%.-   Number of lashes: Increased numbers of lashes are observed in the    treated eye of each patient. In areas where there are a large number    of lashes in the control eye, the increased number of lashes in the    treated eye gave the lashes on the treated side a more thickly    matted overall appearance.-   Auxiliary lash-like hair growth: Several patients have an apparent    increase in lash-like hair in transitional areas adjacent to areas    of normal lash distribution. These prominent robust appear lash-like    hairs appeared to be of comparable length to the actual lashes.    These long, thick lash-like hairs were present in the central    portion of the lids of several patients in a linear arrangement just    above the lash line. Hairs are present at similar locations in the    control eyes but are by contrast thinner or finer in appearance,    have less luster and pigment and are more flat against the skin of    the lid typical of vellus or intermediate hairs. In several    patients, lash-like terminal hairs grow luxuriantly in the medial    canthal area in the treated eye. In the corresponding control eye,    vellus hairs are seen at the same location. Lash-like hairs are also    present in the lateral canthal area of the treated eye but not the    control eye in several subjects. Large lashes are not normally    present at the lateral canthus and the area is generally free of all    but a few occasional very fine lashes or vellus hairs.-   Increased growth of vellus hair on lids: Fine microscopic vellus    hair is present on the skin of the lids and is easily seen with the    slit lamp biomicroscope. This vellus hair is typically denser    adjacent to and below the lateral portion of the lower lids. While    remaining microscopic, vellus hairs are increased in number appear    more robust and are much longer and thicker in treated than in    control eyes in the areas below and lateral to the lower lid.-   Perpendicular angulation of hairs: In areas where there are    lash-like hairs above the lash line and in the medial and lateral    canthal areas, the hairs are much longer, thicker and heavier. They    also leave the surface of the skin at a more acute angle, as though    they are stiffer or held in a more erect position by more robust    follicles. This greater incline, pitch, rise or perpendicular    angulation from the skin surface gives the appearance of greater    density of the hairs.

The foregoing observations will clearly establish that above compositioncan be used to increase the growth of hair in man. This conclusion isbased on the regular and consistent finding of manifestations ofincreased hair growth in treated vs. control areas in human subjects.The conclusion that the composition of this invention is capable ofinducing increased robust growth of hair is based not on a singleparameter, i.e., length, but is based on multiple lines of evidence asdescribed in the results. Detailed examination and description ofmultiple parameters of differences in hair is greatly facilitated by theability to examine the hairs at high magnification under stableconditions of fixed focal length and subject position utilizing thecapabilities of the slitlamp biomicroscope.

Example 13

A topical cream is prepared as follows: Tegacid and spermaceti aremelted together at a temperature of 70-80° C. Methylparaben is dissolvedin about 500 gm of water and propylene glycol, polysorbate 80, andbimatoprost and minoxidil are added in turn, maintaining a temperatureof 75-80° C. The methylparaben mixture is added slowly to the Tegacidand spermaceti melt, with constant stirring. The addition is continuedfor at least 30 minutes with additional stirring until the temperaturehas dropped to 40-45° C. Finally, sufficient water is added to bring thefinal weight to 1000 gm and the preparation stirred to maintainhomogeneity until cooled and congealed.

Example 14

A topical cream is prepared as follows: Tegacid and spermaceti aremelted together at a temperature of 70-80° C. Methylparaben is dissolvedin water and propylene glycol, polysorbate 80, dihydrotestosterone, 0.5to 20%, and bimatoprost, 0.001% to 0.1%, is added in turn, maintaining atemperature of 75-80° C. The methylparaben mixture is added slowly tothe Tegacid and spermaceti melt, with constant stirring. The addition iscontinued for at least 30 minutes with additional stirring until thetemperature has dropped to 40-45° C. Finally, sufficient water is addedto bring the final weight to 1000 gm and the preparation stirred tomaintain homogeneity until cooled and congealed. The composition isapplied to bald human skin once daily to stimulate the growth of hair.

Example 15

A topical cream is prepared as follows: Tegacid and spermaceti aremelted together at a temperature of 70-80° C. Methylparaben is dissolvedin water and propylene glycol, polysorbate 80, dihydrotestosterone, 0.5to 20%, bimatoprost, 0.001% to 0.1%, and/or minoxidil 2% to 5%, areadded in turn, maintaining a temperature of 75-80° C. The methylparabenmixture is added slowly to the Tegacid and spermaceti melt, withconstant stirring. The addition is continued for at least 30 minuteswith additional stirring until the temperature has dropped to 40-45° C.Finally, sufficient water is added to bring the final weight to 1000 gmand the preparation stirred to maintain homogeneity until cooled andcongealed. The composition is applied to bald human skin once daily tostimulate the growth of hair.

Example 16

A topical cream is prepared as follows: Tegacid and spermaceti aremelted together at a temperature of 70-80° C. Methylparaben is dissolvedin water and propylene glycol, polysorbate 80, dihydrotestosterone, 0.5to 20%, bimatoprost, 0.001% to 0.1%, and/or minoxidil 2% to 5%, and/ortestosterone 1% to 20%, are added in turn, maintaining a temperature of75-80° C. The methylparaben mixture is added slowly to the Tegacid andspermaceti melt, with constant stirring. The addition is continued forat least 30 minutes with additional stirring until the temperature hasdropped to 40-45° C. Finally, sufficient water is added to bring thefinal weight to 1000 gm and the preparation stirred to maintainhomogeneity until cooled and congealed.

The composition is applied to bald human skin once daily to stimulatethe growth of hair.

Example 17

An ointment containing bimatoprost and minoxidil is prepared as follows:

-   White petrolatum and wool fat are melted, strained and liquid    petrolatum is added thereto. The bimatoprost, minoxidil, zinc oxide,    and calamine are added to the remaining liquid petrolatum and the    mixture milled until the powders are finely divided and uniformly    dispersed. The mixture is stirred into the white petrolatum, melted    and cooled with stirring until the ointment congeals. The foregoing    ointment can be applied topically to mammalian skin for increased    rate of hair growth, and can be prepared by omitting the zinc oxide    and calamine.

Example 18

A dermatological ophthalmic ointment containing bimatoprost andminoxidil is prepared by adding the active compounds to light liquidpetrolatum. White petrolatum is melted together with wool fat, strained,and the temperature adjusted to 45-50° C. The liquid petrolatum slurryis added and the ointment stirred until congealed. Suitably the ointmentis packaged in 30 gm tubes. The foregoing ointment can be applied to theeyelid to enhance the growth of eyelashes. Similarly the composition canbe applied to the brow for eyebrow growth.

Example 19

An aqueous solution containing bimatoprost and minoxidil is prepared asfollows. bimatoprost and minoxidil are dissolved in water and theresulting solution is sterilized by filtration. The solution isaseptically filled into sterile containers.

The composition so prepared can be used in the topical treatment ofbaldness by application to the scalp daily.

Example 20

Bimatoprost and minoxidil are dissolved in a vehicle ofN-methylpyrrolidone and propylene glycol. The composition can be usedfor application to dogs or cats having hair loss due to mange oralopecia of other causes.

Example 21

An aerosol containing approximately 0.03% by weight bimatoprost and 5%,by weight minoxidil is prepared by dissolving the bimatoprost andminoxidil in absolute alcohol. The resulting solution filtered to removeparticles and lint. This solution is chilled to about minus 30° C. Tothe solution is added a chilled mixture of dichlorodifluoromethane anddichlorotetrafluoroethane. Thirteen ml plastic-coated amber bottles arecold filled with 11.5 gm each of the resulting solution and capped. Thecomposition can be sprayed on the scalp daily to stimulate the growth ofhair.

Example 22

A foamable liquid composition containing approximately 0.03% by weightbimatoprost and 5%, by weight minoxidil is prepared by dissolving thebimatoprost and minoxidil in an alcohol-containing solvent. Saidfoamable liquid composition further includes a solvent system, asurfactant and a foam stabilizer. The solvent system, includes water, analcohol and, optionally, an acid and a water soluble solvent. Thiscomposition is prepared by methods known in the art. A method ofdelivering a foam product according to the present invention comprisesthe following steps: providing a foamable liquid composition comprising5 percent, by weight, minoxidil and 0.03 percent, by weight, bimatoprostor a pharmaceutically acceptable salt of either or both of minoxidil orbimatoprost, in an amount or amounts sufficient to provide: 5 percent,by weight, minoxidil, and 0.03 percent, by weight, bimatoprost in acontainer adapted for dispensing the foamable liquid composition as afoam and dispensing the foamable liquid composition as a foam from saidcontainer onto the skin of a patient. Alternatively, minoxidil may beused in an amount of from 0.5 to 10 percent and preferably in an amountof from 2 to 5 percent, by weight, relative to the total weight of thefoamable liquid composition. Bimatoprost may be used in an amount offrom 0.01 to 3 percent and more preferably in an amount of from 0.03 to1 percent, by weight, relative to the total weight of the liquidcomposition. The solvent system is an aqueous-alcoholic medium, whichenables solubilization of minoxidil and bimatoprost. In one example, thefoamable liquid composition includes from 30 to 80 percent water, byweight. Preferably the foamable liquid composition comprises from 30 to60 percent water, by weight. Preferably, the foamable liquid compositionfurther includes an acid at a concentration of from 0.5 to 5 percent, byweight, of the foamable liquid composition. The acid may be selectedfrom the group consisting of an inorganic acid, an organic acid withchain length of eight carbons or less and mixtures thereof. A preferredfoamable liquid composition includes from 1 to 4 percent, by weight,lactic acid, from 1 to 50, preferably from 5 to 30 percent, by weight,of an alcohol having from one to four carbon atoms, such as methanol,ethanol, propanol and mixtures thereof, and one or more water solublesolvents, such as butylene glycol, glycerin, polyglycerin, ethyleneglycol, and propylene glycol. Preferably, said alcohol is ethanol andpreferably said water soluble solvent is propylene glycol in an amountof from 1 to 20 percent, by weight, and more preferably from 5 to 15percent, by weight, of the foamable liquid composition. The liquid foamcomposition according to the invention contains at least one surfactant.Preferably, the foamable liquid composition comprises from 0.1 to 5percent, by weight, of a surfactant, more preferably from 0.2 to 1percent, by weight of a surfactant. Suitable surfactants haveemulsifying, solvating, and foam-forming or foam-stabilizing properties;are preferably nonionic; and have a hydrophilic-lipophilic balance (HLB)value of greater than about fifteen. In particular, the surfactantoleth-20 is preferred in an amount of from 0.1 to 5 percent, by weight,of the foamable liquid composition and more preferably from 0.2 to 1percent, by weight, of the foamable liquid composition.

Other surfactants optionally used with the present formulation include,but are not limited to: any combination of anionic, cationic, non-ionic,or amphoteric surfactants with an HLB value of greater than fifteen.

Optionally, the foam formed is maintained with a foam stabilizer. In thetreatment of the human scalp for androgenic alopecia the maintenance offoam is important to allow a known and suitable period of contact of theminoxidil and bimatoprost with the scalp. The foam stabilizer ispreferably included in the foamable liquid composition in an amount offrom 0.05 to 0.5 percent, and more preferably from 0.1 to 0.5 percent,by weight.

In particular, the stabilizer includes lauryl glucoside in an amount offrom 0.05 and 0.5% by weight and more preferably from 0.1 to 0.5percent, by weight, of the foamable liquid composition.

Other optional foam stabilizers used with the present liquid compositioninclude, but are not limited to: fatty amine oxides, a quaternaryamines, or a cellulose derivatives, such as methyl cellulose and ethylcellulose.

The liquid composition can be sprayed on the scalp daily to stimulatethe growth of hair.

Example 23

A gel comprising bimatoprost and minoxidil in apharmaceutically-acceptable solvent comprising propylene glycol andalcohol and a cross-linked acrylic polymer thickening agent such as aCarbomer, e.g. Carbomer 934P, is prepared as described below. Thecross-linked acrylic polymer thickening agent is neutralized with aneutralizing agent such as diisopropanolamine.

The gel comprises from 0.0000001% to 10% bimatoprost and from 0.001% to10% minoxidil, by weight. More preferably said gel comprises from 0.01%to 0.5% bimatoprost and from 1% to 5% minoxidil, by weight, mostpreferably said composition comprises 0.03% bimatoprost and 5%minoxidil, by weight.

Said pharmaceutically acceptable solvent is selected from the groupconsisting of ethanol, propanol, butanol, propylene glycol, dipropyleneglycol, hexylene glycol, 1,3-butylene glycol, PEG-200, PEG-400, glyceroland mixtures thereof.

Most preferably, said solvent is selected from the group consisting ofethanol and isopropanol.

Alternatively, said solvent selected from the group consisting ofpropylene glycol, dipropylene glycol, hexylene glycol, 1,3-butyleneglycol, PEG-200, PEG-400, and glycerol.

Most preferably, said solvent is propylene glycol.

In a second alternative embodiment of the invention, said solventcomprises a mixture comprising a first solvent selected from the groupconsisting of ethanol, propanol and butanol and a second solventselected from the group consisting of propylene glycol, dipropyleneglycol, hexylene glycol, 1,3-butylene glycol, PEG-200, PEG-400, andglycerol.

Preferably, in said second alternative embodiment of the invention, saidsolvent comprises a mixture of ethanol and propylene glycol.

The gel further comprising a neutralizing agent, wherein saidneutralizing agent may be selected from the group consisting of ammoniumhydroxide, arginine, 2-amino-2-methyl-1-propanol, dimethanolamine,dibutanolamine, diisobutanolamine, tributanolamine, triisobutanolamine,tri-sec-butanolamine, tripropylamine, ethanolamine, diethanolamine,triethanolamine, PEG-15 cocamine, diisopropanolamine,methylethanolamine, diisopropylamine, dipropylenetriamine, tromethamine,isopropylamine ethylene diamine, triisopropanolamine, tetrahydroxypropylethylenediamine, trimethamine, 2-aminobutanol, aminoethyl propanediol,aminomethyl propanediol, aminomethyl propanol, sodium hydroxide, andpotassium hydroxide.

A pharmaceutically elegant gel comprising minoxidil and bimatoprost isprepared by mixing the below-described mixtures:

Ingredient % w/w Part I Purified water USP q.s. 100 Carbopol□ ® 934P0.45 Part II Bimatoprost 0.03 Minoxidil 5 propylene glycol USP 10alcohol USP 13 diisopropanolamine NF 0.45 Part III alcohol USP 27

What is claimed is:
 1. A method for promoting or enhancing facial hairgrowth, comprising topically administering an effective amount of apharmaceutically acceptable formulation of dihydrotestosterone to atarget skin area, which is the mustache region, beard region, or both ofan adult human male, who has completed puberty, and who is unable togrow full beards and/or mustaches, and wherein the target skin area hassparse mature terminal hair and the human male has a level ofcirculating total serum testosterone that is within a normal physiologicreference range, thereby promoting or enhancing growth of matureterminal hair at the target skin area.
 2. The method of claim 1, whereinthe dihydrotestosterone formulation is applied daily.
 3. The method ofclaim 1, wherein the dihydrotestosterone formulation is in the form of aliquid, lotion, cream, ointment, gel, foam, aerosol, or spray.
 4. Themethod of claim 1, wherein the dihydrotestosterone formulation comprisesas a further active ingredient an additional androgen.
 5. The method ofclaim 4, wherein the additional androgen is testosterone.
 6. The methodof claim 5, wherein the concentration of testosterone in thedihydrotestosterone formulation ranges from about 1% to about 25% w/v.7. The method of claim 1, wherein the dihydrotestosterone formulationcomprises one or more dermal penetration enhancement agents thatoptimize hair shaft absorption of the topically applieddihydrotestosterone formulation and absorption into the hair folliclestructures in a targeted manner and then lead to the drug delivery ofthe topically applied dihydrotestosterone via the hair shaft and via thehair follicle structures to the hair follicle bulb and the dermalpapilla cells of the hair follicle located in the hair follicle bulb;and wherein hair follicle structures can be reservoirs for appliedformulations.
 8. The method of claim 1, wherein a dermal penetrationenhancement agent comprises methanol, ethanol, propanol, isopropanol, orany combination thereof; and wherein the dihydrotestosterone formulationis delivered to the hair follicle by trans-epidermal diffusion in atargeted manner.
 9. The method of claim 1, wherein thedihydrotestosterone formulation comprises benzalkonium chloride in arange of about 0.2 mg/mL to 0.5 mg/mL.
 10. The method of claim 1,wherein the dihydrotestosterone formulation comprises sodium chloride,dibasic sodium phosphate, citric acid, purified water, or anycombination thereof.
 11. The method of claim 1, wherein thedihydrotestosterone is applied topically to achieve targeted delivery ofdihydrotestosterone to the hair follicle bulbs and mesenchymal dermalpapilla cells with minimal drug reaching the systemic circulation. 12.The method of claim 1, wherein the generally accepted normal physiologicreference range of total serum testosterone is about 300 ng/dL to about1000 ng/dL in human males who have completed puberty.
 13. A method forpromoting or enhancing facial hair growth, comprising topicallyadministering an effective amount of a pharmaceutically acceptableformulation of dihydrotestosterone to a target skin area, or areas, ofthe mustache region, beard region, or both of an adult human male, whohas completed puberty, who is unable to grow a robust and full beardand/or mustache, wherein the target skin area, or areas, has or havesparse mature terminal hair growth and the human male does not sufferfrom below normal levels of circulating total serum testosterone,thereby promoting or enhancing growth of mature terminal hair at thetarget skin area, or areas; and wherein the dihydrotestosterone istargeted to the hair shaft and the hair follicle structures with thegoal of dihydrotestosterone delivery to the hair follicle bulbs andmesenchymal dermal papilla cells located in the hair follicle bulb area,with minimal drug reaching the systemic circulation.
 14. The method ofclaim 13, wherein the below normal level of total serum testosterone isbelow the generally accepted lower limit of 300 ng/dL in a human malewho has completed puberty.